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Sep 11, 2016

New drug clears malaria from mice in a single dose

Hasn't been tested in humans yet, but it looks very promising.

John Timmer

Enlarge/ The drug is what chemists might refer to as a bit of a beast.

John Timmer

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Last year, there were over 200 million
cases of malaria, and they resulted in nearly half a million deaths.
Efforts to control the disease have had limited success. The mosquitos
that carry it have rapidly evolved resistance to insecticides like DDT,
and there are now areas of the globe where the parasite that causes the
disease are resistant to even our most effective treatment.

Efforts to develop new drugs are challenging. The malarial parasite, Plasmodium,
is a eukaryote like us, and thus it shares a lot of basic biochemistry.
That makes it harder to find a drug that targets the parasite but not
human cells. Plasmodium also has
a complex life cycle, with stages that are rather distinct. That makes
generating vaccines difficult, and it ensures some treatments only work
on a subset of these stages.

But new approaches to screening drugs have
turned up a number of promising leads in recent years. One success,
reported this week in Nature, involves a drug that targets a Plasmodium protein that no other drug works on. In tests on mice, the drug was able to clear an infection with a single dose.

The report comes from a huge international
collaboration with the scale to match: the team screened approximately
100,000 new chemicals for activity against malaria. These weren't just
any chemicals, either; instead, they were specifically designed to adopt
three-dimensional structures that are similar to those of known
biomolecules. The idea is that this would make it more likely that the
chemicals tested could stick to a protein by occupying a site that the
protein normally uses to interact with a chemical found inside cells.
Ideally, the binding of the drug would disrupt the normal activity of
the protein.

Each of the drugs was tested for its ability
to slow down parasite growth in cultured red blood cells. Four different
sets of related chemicals came out of the screen. Three of them bound
to proteins that are already targets of known drugs. So, while they
could end up being useful, they're not anything new.

The fourth chemical, however, was something
entirely new, and nobody knew what it was sticking to. The structure of
the chemical doesn't provide many clues, given it's got a large series
of rings, some of them with unusual numbers of carbon atoms. So to
figure out how it worked, the team intentionally used low doses of the
drug for a few months to allow Plasmodium
to evolve resistance to it. Once the parasite survived the drug, they
sequenced its genome, looking for changes that could be associated with
the resistance.

The gene they came up with encodes a protein
that helps attach amino acids to RNA, a step that's essential for
getting them incorporated into proteins. In this case, the protein
helped attach phenylalanine to RNA; phenylalanine is an amino acid with a
ring structure, which may explain how the drug could interfere with its
metabolism.

The problem with the drug as it was originally
isolated was that it didn't dissolve well in water. So the team tested a
number of derivatives, one of which was much more water soluble. When
this drug was given to mice, its half-life in the blood was 36
hours—enough time for a single dose to persist for several days.

This revised chemical was also tested in mice,
which didn't complain of any side effects (nor were there any
indication of any). A single dose of the drug was able to completely
clear any sign of infection from the mice. It was also effective when
ingested orally. The drug appeared to work against several different
stages of the parasite's life cycle as well, clearing infections from
both the blood and the liver. Given its effectiveness, the authors also
suggest that it could help limit the spread of the parasite back to
mosquitos.

But the main thing the researchers are excited
about is the single dose. Malaria, including the drug-resistant
varieties, is most prevalent in areas where the medical facilities are
sparse or nonexistent. Getting people in those areas to successfully
complete a course of treatment is a real challenge—one where failure
encourages the evolution of drug resistance. Being able to clear the
parasite with a single dose could solve that problem.

Obviously, there's still a lot of human
testing that will be needed. But with results this promising, that
testing is almost certainly to be in the works.